The invention relates, as novel and useful industrial products, to biaromatic compounds in which the aromatic nuclei are connected by a propynylene or allenylene divalent radical. It also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine or alternatively in cosmetic compositions.
The compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and they find applications more particularly in the topical and systemic treatment of dermatological conditions linked to a keratinization disorder, dermatological conditions (and the like) with an inflammatory and/or immunoallergic component, and dermal or epidermal proliferation, whether benign or malignant. These compounds can, in addition, be used in the treatment of degenerative diseases of the connective tissue, for combating skin ageing, whether photoinduced or chronologic, and treating cicatrization disorders. Furthermore, they find an application in the ophthalmological field, in particular in the treatment of corneopathies.
It is also possible to use the compounds according to the invention in cosmetic compositions for body and hair hygiene.
EP-061,258 has already disclosed biaromatic compounds, the aromatic nuclei of which are connected by a propynylene divalent radical, as substances which are active in pharmaceutical or cosmetic compositions.
The compounds according to EP-661,258 correspond to the following general formula: 
in which:
Ar is an aromatic divalent radical optionally substituted by an R5 radical or a heteroaromatic divalent radical optionally substituted by an R6 radical when the heteroatom is nitrogen,
R1 represents H, xe2x80x94CH3, xe2x80x94CH2OR6, xe2x80x94OR6, xe2x80x94COR7 or xe2x80x94S(O)tR9, t being 0, 1 or 2,
R2 and R3 represent H, C1-C20 alkyl, xe2x80x94OR6 or xe2x80x94SR6,
or R2 and R3, taken together, form a 5- or 6-membered ring optionally substituted by methyl groups and/or optionally interrupted by an oxygen or sulphur atom,
R4 and R5 represent H, a halogen, a lower alkyl
xe2x80x83or xe2x80x94OR6,
R6 represents H, lower alkyl or xe2x80x94COR9,
R7 represents H, lower alkyl, 
xe2x80x83or xe2x80x94OR8,
R8 represents H, C1-C20 a alkyl, which can be linear or branched, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar or amino acid or peptide residue,
R9 represent lower alkyl,
R and Rxe2x80x2 represent H, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl or a sugar, amino acid or peptide residue or R and Rxe2x80x2, taken together, form a heterocycle, and
X represents a divalent radical which, from right to left or vice versa, has the formula: 
in which:
R10 represents H, lower alkyl or xe2x80x94OR6,
R11 representing xe2x80x94OR6,
or R10 and R11, taken together, form an oxo (xe2x95x90O) radical,
and the salts of the said compounds of above formula, when R1 represents a carboxylic acid functional group, and the optical and geometrical isomers of these said compounds.
The compounds according to the present invention, with respect to those of EP-601,258, are essentially distinguished in that the xe2x80x94Xxe2x80x94Arxe2x80x94R1 substituent is at the ortho position with respect to the R2 radical or to the 5- or 6-membered ring when R2 and R3 are taken together, whereas, in ES-661,258, the xe2x80x94Xxe2x80x94Arxe2x80x94R1 substituent is found at the meta position.
This is because it has been found, unexpectedly and surprisingly, that this modification in structure makes it possible to significantly increase the pharmaceutical and cosmetic properties thereof and, in addition, to decrease certain side effects thereof.
The subject-matter of the present invention is therefore novel compounds which can be represented by the following general formula: 
in which:
Ar represents a radical chosen from the following formulae (a) to (c): 
Z being an oxygen or sulphur atom,
R1 represents xe2x80x94CH3, xe2x80x94CH2xe2x80x94Oxe2x80x94R6, xe2x80x94OR6 or xe2x80x94COR7,
R2 represents xe2x80x94OR8, xe2x80x94SR8 or a polyether radical, if, in the latter case, R4 represents linear or branched C1-C20 alkyl and is at the ortho or meta position with respect to the Xxe2x80x94Ar bond,
R3 represents lower alkyl, or
R2 and R3, taken together, form a 5- or 6-membered ring optionally substituted by at least one methyl and/or optionally interrupted by an oxygen or sulphur atom,
R4 represents H, a halogen, linear or branched C1-C20 alkyl, xe2x80x94OR8, a polyether radical or aryl,
R5 represents H, a halogen, linear or branched C1-C20 alkyl or an xe2x80x94OR8 radical,
R6 represents H, lower alkyl or a xe2x80x94COR9 radical,
R7 represents H, lower alkyl, 
xe2x80x83or xe2x80x94OR10,
R8 represents H, lower alkyl or xe2x80x94COR9,
R9 represents lower alkyl,
R10 represents H, C1-C20 alkyl, which can be linear or branched, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar residue,
rxe2x80x2 and rxe2x80x3 represent H, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, or an amino acid or sugar residue or, taken together with the nitrogen atom, form a heterocycle,
X represents a divalent radical which, from right to left or vice versa, has the formula: 
R11 representing H or xe2x80x94OR6, R6 having the same meaning as above,
R12 representing H or lower alkyl, or
R11 and R12, taken together, form an oxo (xe2x95x90O) radical,
and the sales of the compounds of formula (I), when R1 represents a carboxylic acid functional group, and the optical and geometrical isomers of the said compounds of formula (I).
When the compounds according to the invention are provided in the form of a salt, it is preferably a salt of an alkali metal or alkaline earth metal or alternatively of zinc or of an organic amine.
According to the present invention, lower alkyl is understood to mean a C1-C6 radical, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
C1-C20 alkyl, which can be linear or branched, is understood to mean in particular the methyl, ethyl, propyl, isopropyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, dodecyl, hexadecyl and octadecyl radicals.
Monohydroxyalkyl is understood to mean a radical preferably having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
Polyhydroxyalkyl is understood to mean a radical preferably having 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxy-pentyl radicals or the pentaerythritol residue.
Polyether radical is understood to mean a radical having from 1 to 6 carbon atoms and from 1 to 3 oxygen or sulphur atoms, such as the methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether radicals.
Aryl is understood to mean a pyridyl radical, a thiophenyl radical or a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl, one nitro functional group, one lower alkyl, one CF3 radical, one amino radical optionally protected by an acetyl functional group or optionally substituted by one or two lower alkyl(s), one alkoxy radical or one polyether radical. Aryl is preferably understood to mean a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl, one nitro functional group, one lower alkyl, one CF3 radical, one amino radical optionally protected by an acetyl functional group or optionally substituted by one or two lower alkyl(s), one alkoxy radical or one polyether radical, the latter being as defined above.
When the substituent is an alkoxy radical, the latter is preferably a C1-C12 alkoxy radical, such as in particular the methoxy, ethoxy, propyloxy, isopropyloxy, hexyloxy, heptyloxy, octyloxy and nonyloxy radicals.
Aralkyl is preferably understood to mean the benzyl or phenethyl radical optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional group.
Alkenyl is understood to mean a radical preferably having 2 to 5 carbon atoms and exhibiting one or more ethylenic unsaturations, such as more particularly the allyl radical.
Sugar residue is understood to mean a residue deriving in particular from glucose, galactose, mannose or glucuronic acid.
Amino acid residue is understood to mean in particular a residue deriving from lysine, glycine or aspartic acid and peptide residue is understood to mean more particularly a dipeptide or tripeptide residue resulting from the combination of amino acids.
Heterocycle is preferably understood to mean a piperidino radical, a morpholino radical, a pyrrolidino radical or a piperazino radical optionally substituted at the 4-position by a lower C1-C5 alkyl or a mono- or polyhydroxyalkyl, as defined above.
When R4 and R5 represent a halogen, the latter is preferably a fluorine, chlorine or bromine atom.
According to a preferred embodiment, the compounds according to the invention correspond to the following general formula: 
in which:
Ar represents a radical of following formula (a) or (b): 
R1 represents xe2x80x94COR7,
R5 and R7 being as defined above for the formula (I),
X represents a divalent radical which, from right to left or vice versa, has the formula: 
R11 and R12 represent H,
R13 and R14, which are identical or different, represent H or xe2x80x94CH3,
Y represents an oxygen or sulphur atom or a methylene, ethylidene or isopropylidene divalent radical, and
n is 1 or 2.
Mention may in particular be made, among the compounds corresponding to the above formulae (I) and (II) according to the present invention, of the following:
Methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate,
2-Hydroxy-4-[3-(4,4-dimethylchroman-8-yl)-prop-1-ynyl]benzoic acid,
Methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate,
2-Hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoic acid,
Methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate,
2-Hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoic acid,
Ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]-benzoate,
4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]benzoic acid,
4-[3-(5,5,8,8-Tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]benzoic acid,
Ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-ynyl]benzoate,
4-[3-(4,4-Dimethylthiochroman-5-yl)-3-hydroxyprop-1-ynyl]benzoic acid,
4-[3-(4,4-Dimethylthiochroman-5-yl)prop-1-ynyl]benzoic acid,
Ethyl 4-[3-(3,5-di-tert-butyl-2-(methoxymethoxy)phenyl)-3-hydroxyprop-1-ynyl]benzoate,
4-[3-(3,5-D-tert-butyl-2-(methoxymethoxy)-phenyl)-3-hydroxyprop-1-ynyl]benzoate,
Ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-hydroxyprop-1-ynyl]benzoate,
Ethyl-4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-1-ynyl]benzoate,
Ethyl-4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-ynyl]benzoate,
4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-ynyl]benzoic acid,
4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)prop-1-ynyl]benzoic acid,
Ethyl 4-[3-(5-tert-butyl-4-(methoxymethoxy)-biphenyl-3-yl)-3-hydroxyprop-1-ynyl]benzoate,
4-[3-(5-tert-Butyl-4-(methoxymethoxy)-biphenyl-3-yl)-3-hydroxyprop-1-ynyl]benzoic acid,
Ethyl 4-[4-(5-tert-butyl-4-methoxybiphenyl-3-yl)3-hydroxyprop-1-ynyl]benzoate,
4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-ynyl]benzoic acid,
Ethyl 4-[3-(3,5-di-tert-butyl-2-methoxy-phenyl)-3-methoxyprop-1-ynyl]benzoate,
4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)-3-methoxyprop-1-ynyl]benzoic acid,
Methyl 4-[3-(4,4-dimethylthiochroman-8-yl)-prop-1-ynyl]benzoate,
Ethyl 6-[3-(4,4-dimethylthiochroman-8-yl)-prop-1-ynyl]nicotinate,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-ynyl]benzaldehyde,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-ynyl]phenol,
Ethyl 4-[3-(5-tert-butyl-4-hydroxybiphenyl-3-yl)-3-hydroxyprop-1-ynyl]benzoate,
4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)prop-1-ynyl]benzoic acid,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-ynyl]benzoic acid,
4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-1-naphthyl)prop-1-ynyl]benzoic acid,
2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-naphthyl)prop-1-ynyl]benzoic acid,
Methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate,
2-Hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoic acid,
2-Hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoic acid,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-ynyl]benzamide,
N-Ethyl-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzamide,
N-(4-Hydroxyphenyl)-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzamide,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-ynyl]benzoic acid morpholide,
4-[3-(4,4-Dimethylthiochroman-8-yl)prop-2-ynyl]benzoic acid,
4-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-1-yl)prop-2-ynyl]benzoic acid,
4-[3-(4,4-Dimethyl-6-phenylthiochroman-8-yl)prop-1-ynyl]benzoic acid,
4-[3-(4,4-Dimethyl-6-phenylchroman-8-yl)prop-1-ynyl]benzoic acid,
4-[3-(4,4-Dimethyl-6-phenylthiochroman-8-yl)prop-2-ynyl]benzoic acid,
4-[3-(4,4-Dimethyl-6-(p-tolyl)thiochroman-8-yl)prop-1-ynyl]benzoic acid,
4-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-1-yl)prop-2-ynyl]benzoic acid,
4-[3-(5,5,8,8-Tetramethyl-3-(p-tolyl)-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]benzoic acid,
4-(3-[3-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-1-yl]prop-1-ynyl)-benzoic acid,
2-Hydroxy-4-[3-(5,5,8,8-tetramethyl-3-(p-tolyl)-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]-benzoic acid, and
3-Hydroxy-4-[3-(5,5,8,8,-tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphth-1-yl)prop-1-ynyl]benzoic acid.
Another subject-matter of the present invention is the processes for the preparation of the compounds of formula (I) above according to the reaction scheme given in Table A.
The compounds of formula (I) can be prepared from a halogenated derivative (1), preferably a brominated or iodinated derivative, by conversion into the magnesium derivative, then reaction with methoxyallene in the presence of CuBr and production of the propargyl derivative (2). The latter is subsequently coupled with a halogenated derivative (3), preferably an iodinated or brominated derivative, in the presence of a palladium catalyst, for example bis(triphenyl-phosphine)palladium(II) chloride, in a solvent, such as triethylamine.
The compounds of formula (I) can also be prepared by a sequence of reactions comprising the reaction of lithium trimethylsilylacetylide with an aldehyde compound (4) and deprotection with tetrabutyl-ammonium fluoride in THF, producing the propargyl alcohol (6). By coupling of the latter with a halogenated derivative (3), preferably an iodinated or brominated derivative, in the presence of a palladium catalyst, for example bis(triphenylphosphine)palladium(II) chloride, in a solvent, such as triethylamine, the hydroxylated compound according to the invention of formula (Ixe2x80x2) is obtained. The latter, by reduction of the alcohol functional group to carbide in the presence of trimethylsilyl iodide in a solvent, such as hexane, or by hydride transfer from a silane, such as triethylsilane, in the present of BF3xc2x7Et2 O in a chlorinated solvent, such as methylene chloride, results in the compound of formula (I).
The compounds of formula (I) can also be prepared by a sequence of reactions comprising the reaction of a benzoyl chloride of formula (8) with an acetylenic derivative of formula (9) in the presence of a Lewis acid (for example AlCl3) in a chlorinated solvent, such as dichloromethane. The acetylenic ketone (10) thus obtained is reduced to the hydroxylated compound according to the invention (Ixe2x80x2) by the action of an alkali metal hydride, such as sodium borohydride, in an alcoholic solvent (for example methanol). The reduction of the alcohol functional group of (Ixe2x80x2) to carbide is carried out as above and results in the compound of formula (I).
The allene compounds of formula (Ixe2x80x3) can be prepared by heating the compounds of formula (I) in the presence of a base (NaOH, Et3N, DBU) in a solvent, such as heptane or THF.
The starting materials for the synthesis of the preferred compounds or formula (II) can be obtained according to different reaction schemes depending on the meaning of the Y radical.
When Y represents a sulphur atom, R13 and R14 representing xe2x80x94CH3 and n=2, that is to say 4,4-dimethylthiochromanyl derivatives, the latter can be obtained from 2-bromothiophenol by coupling with 4-bromo-2-methyl-2-butene in the presence of potassium carbonate or sodium hydride in DMF and then cyclization, either in the presence of p-toluenesulphonic acid or in the presence of aluminium chloride or of polyphosphoric acid, according to the following reaction scheme: 
When Y represents an oxygen atom, R13 and R14 representing xe2x80x94CH3 and n=2, that is to say 4,4-dimethylchromanyl derivatives, the latter can be obtained from phenol by reaction with 3-methyl-3-buten-1-yl diphenyl phosphate in the presence of stannic chloride, then lithiation in the presence of butyllithium and of tetramethylethylenediamine and reaction with diiodomethane (K. McWilliams, J. Org. Chem., 1966, 61, 7408-14), according to the following reaction scheme: 
When Y represents an isopropylidene radical, R13 and R14 representing xe2x80x94CH3 and n=2, that is to say tetrahydrotetramethylnaphthyl derivatives, the latter can be obtained from 3-bromophenol by reaction with 2,5-dichloro-2,5-dimethylhexane in the presence of aluminium chloride, then hydrogenolysis in the presence of palladium-on-charcoal and of formic acid or of hydrogen and formation of the triflate derivative, and then hydroformylation (H. Kotsuki, Synthesis, 1996, 470-2), according to the following reaction scheme: 
When Y represents a methylene radical R13 and R14 representing xe2x80x94CH3 and n=2, that is to say tetrahydrodimethylnaphthyl derivatives, the latter can be obtained from 2-bromoanisole by coupling with the zinc derivative of 1-bromo-4-methylpent-3-ene in the presence of a palladium catalyst, for example PdCl2/(dppf) (R. L. Danheiser, J. Org. Chem., 1995, 60, 8341-8350), then cyclization in the presence of a Lewis acid, for example aluminium chloride, then demethylation with BBr3, formation of the triflate and hydroformylation as described above.
This sequence of reactions can be represented by the following reaction scheme: 
When R1 represents xe2x80x94COOH, the compounds are prepared while protecting R1 with a protective group of alkyl, allyl or tert-butyl type.
Conversion to the free form can be carried out:
in the case of an alkyl protective group, by means of sodium hydroxide or lithium hydroxide in an alcoholic solvent, such as methanol, or in THF;
in the case of an allyl protective group, by means of a catalyst, such as certain transition metal complexes, in the presence or a secondary amine, such as morpholine;
in the case of a protective group of tert-butyl type, by means or trimethylsilyl iodide.
When R1 is xe2x80x94CH, the compounds can be obtained from the corresponding acid by reduction in the presence of lithium aluminium hydride.
When R1 is 
the compounds can be obtained by conversion of the corresponding acid to the acid chloride, for example with thionyl chloride, and then reaction with ammonia or an appropriate amine.
Another subject-matter of the present invention is, as medicament, the compounds of formula (I) as defined above.
These compounds exhibit activity in the test for differentiation of mouse embryonic teratocarcinoma cells (F9) (Cancer Research, 43, p. 5268, 1983) and/or in the test for inhibition of ornithine decarboxylase after induction with TPA in mice (Cancer Research, 38; p. 793-801, 1978). These tests show the activities of the compounds in the fields of cell differentiation and proliferation respectively.
In the test for differentiation of the cells (F9), it is possible to evaluate an agonist activity, like an antagonist activity, at the retinoic acid receptors. This is because an antagonist is inactive when it is alone in this test but partially or completely inhibits the effect produced by an agonist retinoid on the morphology and on the secretion of the plasminogen activator. These compounds therefore also exhibit activity in a test which consists in identifying RAR-antagonist molecules, as described in French Patent Application No. 95-07302, filed on 19 Jun. 1995 by the Applicant Company. This test comprises the following stages: (i) a sufficient amount of an RAR-agonist molecule is applied topically to part of the skin of a mammal, (II) a molecule capable of exhibiting an RAR-antagonist activity is administered systemically or topically to the same mammal or to the same part of the skin of the mammal, before, during or after stage (i), and (iii) the response on the part of the skin thus treated of the mammal is evaluated. Thus, the response to a topical application to the ear of a mammal of an RAR-agonist molecule, which corresponds to an increase in the thickness of this ear, can be inhibited by the systemic or topical administration of an RAR-antagonist molecule.
The compounds according to the invention are particularly well suited to the following fields of treatment:
1) for treating dermatological conditions linked to a disorder of keratinization involving differentiation and proliferation, in particular for treating acne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, drug or occupational acne,
2) for treating other types of disorders of keratinization, in particular ichthyoses, ichthyosiform conditions, Darier""s disease, palmoplantar keratoderma, leucoplakia and leucoplakiform conditions or cutaneous or mucosal (oral) lichen,
3) for treating other dermatological conditions linked to a disorder of keratinization with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory conditions which do not show disorder of keratinization,
4) for treating all dermal or epidermal proliferations, whether they are benign or malignant and whether they are or are not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, florid or oral papillomatoses and the proliferations which can be induced by ultraviolet radiation, in particular in the case of basal cell and prickle cell epithelioma,
5) for treating other dermatological disorders, such as bullous dermatoses and collagen diseases,
6) for treating certain ophthalmological disorders, in particular corneopathies,
7) for repairing or combating skin ageing, whether photoinduced or chronologic, or for reducing actinic keratoses and pigmentations or any pathology associated with chronologic or actinic ageing,
8) for preventing or treating the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) for preventing or treating disorders of cicatrization or for preventing or for repairing stretch marks,
10) for combating disorders of the sebaceous function, such as hyperseborrhoea of acne or simple seborrhoea,
11) for treating or preventing cancerous or precancerous conditions,
12) for treating inflammatory conditions, such as arthritis,
13) for treating any condition of viral origin at the cutaneous level or the general level,
14) for preventing or treating alopecia,
15) for treating dermatological or general conditions with an immunological component, and
16) for treating conditions of the cardiovascular system, such as arteriosclerosis.
In the therapeutic fields mentioned above, the compounds according to the invention can advantageously be employed in combination with other compounds with an activity of retinoid type, with vitamins D or their derivatives, with corticosteroids, with agents for combating free radicals, with xcex1-hydroxy or xcex1-keto acids or their derivatives, or alternatively with ion-channel blockers. Vitamins D or their derivatives is understood to mean, for example, the derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. Agents for combating free radicals is understood to mean, for example, xcex1-tocopherol, superoxide dismutase or SOD, ubiquinol or certain metal-chelating agents. xcex1-Hydroxy or xcex1-keto acids or their derivatives is understood to mean, for example, lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid or their salts, amides or esters. Finally, ion-channel blockers is understood to mean, for example, minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives.
Another subject-matter of the present invention is pharmaceutical compositions comprising at least one compound of formula (I) as defined hereinabove, one of its optical or geometrical isomers or one of its salts.
The pharmaceutical compositions are intended especially for treating the abovementioned conditions and are characterized in that they comprise, in a pharmaceutically acceptable vehicle which is compatible with the method of administration selected, at least one compound of formula (I), one of its optical or geometrical isomers or one of its salts.
The administration of the compounds according to the invention can be carried out enterally, parenterally, topically or ocularly.
For enteral administration, the compositions can be provided in the form of tablets, hard gelatin capsules, dragxc3xa9es, syrups, suspensions, solutions, powders, granules, emulsions or polymeric or lipid vesicles or nanospheres or microspheres which make possible controlled release. For parenteral administration, the compositions car be provided in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg by body weight, and this at the rate of 1 to 3 intakes.
For topical administration, the pharmaceutical compositions based on the compounds according to the invention are more particularly intended for treating the skin and the mucous membranes and can then be provided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which make possible controlled release of the active principle. These compositions for topical administration can furthermore be provided either in anhydrous form or in aqueous form, according to the clinical indication.
For ocular administration, they are mainly eye washes.
These compositions for topical or ocular use contain at least one compound of formula (I) as defined above or one of its optical or geometrical isomers or one of its salts, at a concentration preferably of between 0.001% and 5% by weight with respect to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetics field, in particular in body and hair hygiene, and especially for the treatment of skin with a tendency to develop acne, for hair regrowth and combating hair loss, for combating the greasy appearance of the skin or the hair, in protecting against the deleterious effects of sunlight or in the treatment of physiologically dry skin, and for preventing and/or for combating photoinduced or chronologic ageing.
In the cosmetics field, the compounds according to the invention can furthermore be advantageously employed in combination with other compounds with an activity of retinoid type, with D vitamins or their derivatives, with corticosteroids, with agents for combating free radicals, with xcex1-hydroxy or xcex1-keto acids or their derivatives, or alternatively with ion-channel blockers, all the latter compounds being as defined above.
Another subject matter of the present invention is thus a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable vehicle, at least one compound of formula (I) as defined above or one of its optical or geometrical isomers or one of its salts, it being possible for the said cosmetic composition to be provided in particular in the form of a cream, a milk, a lotion, a gel, polymeric or lipid vesicles or nanospheres or microspheres, a soap or a shampoo.
The concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight with respect to the total weight of the composition.
The pharmaceutical and cosmetic compositions according to the invention can additionally contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and especially: wetting agents; depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating agents, such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea; anti-seborrhoeic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide; antibiotics, such as erythromycin and its esters, neomycin, clindamycin and its esters, or tetracyclins; antifungal agents, such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth, such as minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and especially xcex2-carotene; anti-psoriatic agents, such as anthralin and its derivatives; and finally eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides.
The compositions according to the invention can also contain flavour enhancers, preserving agents such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and antioxidants such as xcex1-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
A number of examples of the preparation of active compounds of formula (I) according to the invention, as well as various pharmaceutical and cosmetic formulations based on these compounds, will now be given by way of illustration and without any implied limitation.